Schizophrenia is a devastating illness, known to be genetically mediated;however, no gene has been significantly associated with the illness at genome wide significance levels in published meta-analyses. Schizophrenia is also known to be a disconnection syndrome, whereby abnormal white matter tracts in the brain are thought to contribute to the development of the illness. We seek to elucidate the genetic basis of schizophrenia by studying variations in white matter tracts found to be involved in schizohprenia. In order to study the white matter tracts, we will use diffusion weighted imaging in a large sample of healthy monozygotic and dizygotic twins (N=1150) with detailed genome wide genotype data to study the relation between genetic polymorphisms and tract integrity and geometry. This unique population will allow us to determine the heritability, or the degree of genetic mediation, of these tracts of interest. For those tracts which have properties that are highly heritable, we will be able to associate genetic polymorphisms of these individuals with the tracts of interest. We will then have identified genes involved with variations of tract integrity and geometry which then will also be associated with schizophrenia. This will be the first study to take an imaging genomics approach for identifying risk genes: we will survey the entire genome for statistical association to a brain trait of interest. This study will also help provide a biological mechanism for schizophrenia, help discover novel gene targets for therapeutics, provide a more accurate and biologically based diagnostic criterion for the disorder, and provide a method to discover the genetic basis of other mental illnesses that can be generally adopted by the biotechnology community. Public Health Relevance: To identify genes associated with this schizophrenia, we will study a known deficit of the illness: aberrant connections between different brain regions. Using a new technique of brain imaging capable of studying these connections in the living brain, and by studying the entire genome of many healthy individuals, we will be able to find variations in connections that are associated with alterations in the genome. By following this plan, we expect to find novel genes involved in the development of schizophrenia, help to provide a biological mechanism for schizophrenia, help discover targets for therapeutic medications, and provide a more accurate and biologically based diagnostic criterion for the disorder.